AMPK (adenosine monophosphate kinase) is a heterotrimeric, multisubstrate kinase composed of one catalytic (α1 or α2), one regulatory (β1 or β2), and one AMP/ATP binding (γ1, γ2, or γ3) subunit. The C terminus of the β subunit interacts with both α and γ subunits, and current evidence indicates that the β subunit is an obligatory component of the active AMPK complex. The exact mechanism by which AMPK is regulated by the energy status of a cell is not fully understood. It is thought that when intracellular energy levels drop (i.e., when there is a low ATP:AMP ratio), AMP displaces ATP from the γ subunit, causing a conformational change that allows upstream kinases (e.g., LKB1 or CaMKKβ) to phosphorylate and activate the α subunit. Alternatively, AMPK may be constitutively phosphorylated, but is quickly dephosphorylated under normal conditions. At high AMP levels, however, AMP binding leads to a conformational change shielding activation site from such action by phosphatase.
AMPK acts as a sensor of energy status within cells and can be considered a master switch of energy metabolism because, upon activation, the enzyme phosphorylates a number of downstream protein substrates that have an effect on lipid biosynthesis, fatty acid oxidation, glucose uptake, gluconeogenesis and lipogenesis, for example. Phosphorylation of downstream targets by AMPK decreases ATP usage by the cell which, in turn, increases the ATP:AMP ratio in the cell which, in turn, decreases AMPK activity.
All those properties combine to make AMPK an attractive target in the treatment of diabetes, obesity and a variety of other metabolic disorders.